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Peptide therapy prompts responses in diabetes
Immunotherapy using peptides has been successful for some patients with allergies, but has not yet been deployed in autoimmune diseases, which may involve greater safety risks. Alhadj Ali et al. designed a placebo-controlled trial to determine whether a proinsulin peptide could safely elicit immune and metabolic responses in people recently diagnosed with type 1 diabetes without accelerating disease. This small trial showed that treatment seemed to modify T cell responses and did not interfere with residual β cell function. In contrast to subjects in the placebo arm, treated subjects did not need to increase their insulin use. These encouraging results support a larger trial to investigate efficacy of the peptide therapy for treating disease.
Abstract
Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen–DR4(DRB1*0401)–restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group’s daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell–specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.
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